The present invention relates to new heterocycloalkylbenzocyclobutane and heteroarylbenzocyclobutane compounds, and to pharmaceutical compositions containing them.
The compounds of the present invention act as powerful serotonin and noradrenalin reuptake inhibitors. As such, they are useful as medicaments in the treatment of depression, panic attacks, obsessive-compulsive disorders, phobias, impulsive disorders, drug abuse, anxiety, obesity and bulimia.
Indeed, the compounds of the present invention have shown themselves to be active, on the one hand, in vitro in the characterisation test for the inhibition of serotonin and noradrenalin reuptake and, on the other hand, in vivo. Accordingly, in the microdialysis experiments carried out in rat frontal cortex, the compounds of the invention bring about, in that area, an increase in the release of serotonin, noradrenalin and dopamine. The compounds claimed by the Applicant are therefore entirely suited to use in pathologies which are associated with a defect in the transmission of those two neuromediators. That especially valuable effect of the compounds of the invention is also demonstrated in the marble-burying test in mice.
More especially, the present invention relates to compounds of formula (I): 
wherein:

denotes a single bond or a double bond,
n is an integer from 1 to 6 inclusive,
R1 and R2, which may be identical or different, each independently of the other represent a group selected from a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a cycloalkyl group, a cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a heterocycloalkyl group, a heterocycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a heteroaryl group, and a heteroaryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched,
X represents a group selected from xe2x80x94CHxe2x95x90CHxe2x80x94, an oxygen atom, a group S(O)m wherein m is an integer from 0 to 2 inclusive, and NR3 wherein R3 represents a group selected from a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a cycloalkyl group, a cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a linear or branched (C2-C6)alkenyl group, and a linear or branched (C2-C6)alkynyl group,
Y represents a CH or CH2 group depending on whether 
denotes a single bond or a double bond, or may have the additional meaning of an oxygen atom when X represents an oxygen atom,
T represents a monocyclic or polycyclic (C3-C12)cycloalkyl group, wherein one of the carbon atoms of the cycloalkyl may optionally be replaced by a group selected from an oxygen atom, a selenium atom, a group of formula S(O)p wherein p is an integer from 0 to 2 inclusive, NR3 wherein R3 is as defined hereinbefore, and SiR4R5 wherein R4 and R5, which may be identical or different, represent a linear or branched (C1-C6)alkyl group,
their isomers and addition salts thereof with a pharmaceutically acceptable acid or base.
xe2x80x9cAryl groupxe2x80x9d is understood to mean a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl and benzocyclobutyl, it being possible for each of those groups to be optionally substituted by one or more identical or different groups selected from halogen atoms, linear or branched (C1-C6)alkyl groups, hydroxy groups, linear or branched (C1-C6)alkoxy groups, nitro groups, cyano groups, linear or branched trihalo-(C1-C6)alkyl groups, amino groups, monoalkylamino groups in which the alkyl moiety has from 1 to 6 carbon atoms and is linear or branched and dialkylamino groups in which each alkyl moiety has from 1 to 6 carbon atoms and is linear or branched.
xe2x80x9cHeteroaryl groupxe2x80x9d is understood to mean an aryl group as defined hereinbefore, containing within the ring system from one to three identical or different hetero atoms selected from oxygen, nitrogen and sulphur, said heteroaryl group being optionally substituted by one or more identical or different groups selected from the substituents defined above for the aryl group. Among the heteroaryl groups there may be mentioned by way of non-limiting example the groups pyridyl, pyrimidinyl, indolyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl, benzo[1,4]dioxinyl, 2,3-dihydrobenzo[1,4]dioxinyl, etc.
xe2x80x9cCycloalkyl groupxe2x80x9d is understood to mean a mono- or poly-cyclic system, having from 3 to 12 ring members, optionally containing one or more unsaturations, which do not confer an aromatic character upon the said ring system.
xe2x80x9cHeterocycloalkyl groupxe2x80x9d is understood to mean a cycloalkyl group as defined hereinbefore, containing within the ring system from one to three identical or different hetero atoms selected from oxygen, nitrogen and sulphur.
Preferred compounds of the invention are the compounds of formula (I) wherein n has the value 1.
Preferred R1 and R2 substituents according to the invention are the hydrogen atom, the linear or branched (C1-C6)alkyl group, and the group 2,3-dihydro-1,4-benzodioxin-2-ylmethyl.
A preferred substituent T according to the invention is the saturated monocyclic (C3-C8)cycloalkyl group.
Advantageously, preferred substituents T according to the invention are the cyclopentyl and cyclohexyl groups.
According to an advantageous embodiment of the invention, preferred compounds of the invention are the compounds of formula (I/A): 
wherein n, R1, R2 and T are as defined for formula (I), X10 represents an oxygen atom or a sulphur atom, and Y10 represents a CH group.
According to another advantageous embodiment of the invention, preferred compounds of the invention are the compounds of formula (I/B): 
wherein X, Y, n, R1, R2, R3 and T are as defined for formula (I).
Advantageously, preferred compounds of the invention are the compounds of formula (I/B) wherein n is 1, and X represents a group NR3 wherein R3 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group.
According to a third advantageous embodiment of the invention, preferred compounds of the invention are the compounds of formula (I/C): 
wherein n, R1, R2, X and T are as defined for formula (I), and Y20 represents a CH or CH2 group.
According to a fourth advantageous embodiment of the invention, preferred compounds of the invention are the compounds of formula (I/D): 
wherein n, R1, R2, X and T are as defined for formula (I), and Y20 represents a CH or CH2 group.
According to another advantageous embodiment of the invention, preferred compounds of the invention are the compounds of formula (I/E): 
wherein n, R1, R2, X and T are as defined for formula (I), and Y20 represents a CH or CH2 group.
Lastly, according to a final valuable embodiment of the invention, preferred compounds of the invention are the compounds of formula (I/F): 
wherein n, R1, R2, X and T are as defined for formula (I), and Y20 represents a CH or CH2 group.
Preferred compounds of the invention are:
1-{6-[(dimethylamino)methyl]-1-methyl-2,3,5,6-tetrahydro-1H-cyclobuta[f]indol-6-yl}cyclohexanol,
1-{6-[(dimethylamino)methyl]-2,3,5,6-tetrahydro-1H-cyclobuta[f]indol-6-yl}cyclohexanol,
1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzofuran-5-yl}cyclohexanol,
1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-yl}cyclohexanol,
1-{6-[(dimethylamino)methyl]-1-methyl-5,6-dihydro-1H-cyclobuta[f]indol-6-yl}cyclohexanol,
1-{7-[(dimethylamino)methyl]-2,3,6,7-tetrahydro-1H-cyclobuta[e]indol-7-yl}cyclohexanol,
1-{5-[(methylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-yl}cyclopentanol,
1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-yl}cyclopentanol,
(+)-1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-yl}cyclopentanol,
(xe2x88x92)-1-{5-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-5-yl}cyclopentanol,
1-{6-[(dimethylamino)methyl]-5,6-dihydrocyclobuta[f][1]benzothien-6-yl}cyclopentanol,
1-{5-[(dimethylamino)methyl]-1-methyl-5,6-dihydro-1H-cyclobuta[f]indol-5-yl}cyclopentanol,
1-{7-[(dimethylamino)methyl]-6,7-dihydrocyclobuta[g][1]benzofuran-7-yl}cyclopentanol,
1-{1-[(dimethylamino)methyl]-1,2-dihydrocyclobuta[b]naphthalen-1-yl}cyclopentanol,
1-{7-[(dimethylamino)methyl]-6,7-dihydro-3H-cyclobuta[e]indol-7-yl}cyclopentanol,
1-{1-[(dimethylamino)methyl]-1,2-dihydrocyclobuta[a]naphthalen-1-yl}cyclopentanol.
The isomers and addition salts with a pharmaceutically acceptable acid or base of the preferred compounds form an integral part of the invention.
Isomers are understood to be the optical isomers, such as the diastereoisomers and enantiomers.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The present invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material:
a) either a compound of formula (II): 
wherein Xa represents a sulphur atom, an oxygen atom, or an NH group,
which compound of formula (II) is reacted with a compound of formula (III):
Zxe2x80x94CH(OA)2xe2x80x83xe2x80x83(III) 
wherein A represents a linear or branched (C1-C4)alkyl group and Z represents a formyl group (when Xa represents an NH group), or a group xe2x80x94CH2Hal wherein Hal represents a chlorine, bromine or iodine atom,
to yield compounds of formula (IV): 
wherein Xa and A are as defined hereinbefore,
which compounds of formula (IV) are subjected:
either, when Xa has the meaning X1 representing an oxygen atom or a sulphur atom, to conditions of cyclisation by the action of an acid, such as polyphosphoric acid or a Lewis acid, to yield compounds of formula (V/a): 
wherein X1 represents an oxygen atom or a sulphur atom,
which compounds of formula (V/a) are treated:
either, in the presence of a strong base, with a cyclic ketone of formula (VI): 
wherein T has the same meanings as for formula (I),
to yield compounds of formula (VII/a), 
xe2x80x83wherein X1 and T are as defined hereinbefore,
which compounds of formula (VII/a) are subjected to the action of a reducing agent according to conventional conditions of organic synthesis, to yield compounds of formula (I/a), a particular case of the compounds of formula (I): 
wherein X1 and T are as defined hereinbefore,
for which compounds of formula (I/a):
either the primary amine function is substituted according to conventional methods of organic synthesis, such as reductive amination or nucleophilic substitution with a compound of formula (VIIIa):
Rxe2x80x21xe2x80x94Z1xe2x80x83xe2x80x83(VIIIa) 
wherein Rxe2x80x21 has the same meanings as R1 for formula (I) with the exception of the meaning of a hydrogen atom, and Z1 represents a leaving group customary in organic chemistry, such as a halogen atom or a mesylate or tosylate group,
to yield compounds of formula (I/b1), a particular case of the compounds of formula (I): 
wherein X1, T and Rxe2x80x21 are as defined hereinbefore,
or according to an advantageous embodiment of the process, treatment is carried out with a compound of formula (VIIIb):
Rxe2x80x31xe2x80x94COZ2xe2x80x83xe2x80x83(VIIIb) 
wherein Rxe2x80x31 represents a heterocycloalkyl-(C1-C5)alkyl group in which the alkyl moiety is linear or branched, and Z2 represents a chlorine atom or an imidazolyl group, to yield compounds of formula (I/b2): 
wherein X1, T and Rxe2x80x31 are as defined hereinbefore,
which compounds of formula (I/b2) are reduced with a reducing agent conventionally used in organic chemistry, to yield compounds of formula (I/b3): 
wherein X1, Rxe2x80x31 and T are as defined hereinbefore,
the totality of the compounds of formulae (I/b1) and (I/b3) constituting the compounds of formula (I/b),
which compounds of formula (I/b) are treated according to the same conditions as those described hereinbefore with a compound of formula (VIIIc):
Rxe2x80x22xe2x80x94Z1xe2x80x83xe2x80x83(VIIIc) 
wherein Z1 is as defined hereinbefore and Rxe2x80x22 has the same meanings as R2 for formula (I) with the exception of the meaning of a hydrogen atom,
to yield compounds of formula (I/c), a particular case of the compounds of formula (I): 
wherein X1, T, Rxe2x80x21 and Rxe2x80x22 are as defined hereinbefore,
or, in the presence of a strong base, with an amine of formula (IX): 
wherein R1 and R2 are as defined for formula (I), n1 is an integer from 2 to 6 inclusive, and L represents a leaving group, such as a halogen atom, or a mesylate, tosylate or trifluoromethanesulphonate group, to yield compounds of formula (X): 
wherein X1, n1, R1 and R2 are as defined hereinbefore,
which compounds of formula (X) are treated with hydrogen peroxide in the presence of sodium carbonate, to yield compounds of formula (XI): 
wherein X1, n1, R1 and R2 are as defined hereinbefore,
which compounds of formula (XI) are reduced by the action of ammonium formate in the presence of 10% Pd/C, to yield compounds of formula (XII): 
wherein X1, n1, R1 and R2 are as defined hereinbefore,
which compounds of formula (XII) are subjected to the action of a compound of formula (XIII):
(CH3)2Nxe2x80x94CH(OG)2xe2x80x83xe2x80x83(XIII) 
wherein G represents a linear or branched (C1-C6)alkyl group, a benzyl group or a cyclohexyl group,
to yield compounds of formula (XIV): 
wherein X1, n1, R1 and R2 are as defined hereinbefore,
which compounds of formula (XIV) are treated with a dimagnesium compound of formula (XV): 
wherein Hal represents a halogen atom, and T is as defined for formula (I),
to yield compounds of formula (I/d), a particular case of the compounds of formula (I): 
wherein X1, n1, R1, R2 and T are as defined hereinbefore,
the totality of the compounds of formulae (I/a), (I/b), (I/c) and (I/d), in the particular case when X1 represents a sulphur atom, constituting the compounds of formula (I/e): 
wherein n, R1, R2 and T are as defined for formula (I),
which compounds of formula (I/e) are subjected to the action of an oxidising agent according to conventional conditions of organic synthesis, to yield compounds of formula (I/f), a particular case of the compounds of formula (I): 
wherein p1 is an integer selected from 1 and 2, and n, R1, R2 and T are as defined hereinbefore,
the totality of the compounds of formulae (I/a), (I/b), (I/c), (I/d) (wherein X1 represents an oxygen or sulphur atom) and (I/f) constituting the compounds of formula (I/g): 
wherein X1a represents an oxygen atom or a group of formula S(O)p wherein p is as defined for formula (I), and n, R1, R2 and T are as defined for formula (I),
which compounds of formula (I/g) are subjected to the action of a reducing agent according to conventional conditions of organic synthesis, to yield compounds of formula (I/h), a particular case of the compounds of formula (I): 
wherein X1a, n, R1, R2 and T are as defined hereinbefore,
or, when Xa has the meaning Xxe2x80x22 representing an NH group, to the action of a sulphonic acid chloride of formula (XVI):
Exe2x80x94SO2Clxe2x80x83xe2x80x83(XVI) 
wherein E represents a linear or branched (C1-C4)alkyl group, a phenyl group or a p-toluyl group,
to yield compounds of formula (XVII): 
wherein X2 represents a nitrogen atom, and E and A are as defined hereinbefore,
which compounds of formula (XVII) are cyclised by the action of an acid to yield compounds of formula (V/b): 
wherein X2 and E are as defined hereinbefore,
the cyclic amine of which compounds of formula (V/b) is deprotected by the action of a basic agent, which are then subjected to the action of a reducing agent according to conventional conditions of organic synthesis, to yield compounds of formula (V/c): 
wherein X2 is as defined hereinbefore,
which compounds of formula (V/c) are subjected to the action of a compound of formula (VI) as described hereinbefore to yield compounds of formula (VII/b): 
wherein X2 is as defined hereinbefore and T is as defined for formula (I),
which compounds of formula (VII/b) are:
either treated according to the same conditions as those described for the compounds of formula (VII/a), to yield compounds of formula (I/i), a particular case of the compounds of formula (I): 
wherein X2 and T are as defined hereinbefore,
which compounds of formula (I/i) may be treated in succession with a compound of formula (VIIIa) or (VIIIb), and then (VIIIc), as defined hereinbefore, to yield compounds of formulae (I/j) and (I/k), respectively, particular cases of the compounds of formula (I): 
wherein X2, T, Rxe2x80x21 and Rxe2x80x22 are as defined hereinbefore, and Rxe2x80x23 has the same meanings and values as Rxe2x80x21,
the totality of the compounds of formulae (I/i), (I/j) and (I/k) constituting the compounds of formula (I/l): 
wherein X2, R1, R2, R3 and T are as defined for formula (I),
which compounds of formula (I/l) are subjected to the action of an oxidising agent, such as manganese dioxide, to yield compounds of formula (I/m), a particular case of the compounds of formula (I): 
wherein X2, R1, R2, R3 and T are as defined hereinbefore,
or treated with a compound of formula (XVI) as defined hereinbefore, to yield compounds of formula (XVIII): 
wherein T, X2 and E are as defined hereinbefore,
which compounds of formula (XVIII) are reduced according to conventional conditions of organic synthesis, to yield compounds of formula (XIX): 
wherein T, X2 and E are as defined hereinbefore,
the primary amine function of which compounds of formula (XIX) may be substituted by the action of a compound of formula (VIIIa) as defined hereinbefore, to yield compounds of formula (XX): 
wherein T, X2, E and Rxe2x80x21 have the same meanings as those described hereinbefore,
which compounds of formula (XX) may be converted into tertiary amines by the action of a compound of formula (VIIIb) as defined hereinbefore, to yield compounds of formula (XXI): 
wherein T, X2, E, Rxe2x80x21 and Rxe2x80x22 are as defined hereinbefore,
which compounds of formulae (XX) and (XXI) are then deprotected by treatment with sodium in liquid ammonia, to yield compounds of formulae (I/n) and (I/o), respectively, particular cases of the compounds of formula (I): 
wherein T, X2, Rxe2x80x21 and Rxe2x80x22 are as defined hereinbefore,
b) or a compound of formula (II/1): 
wherein Hal represents a halogen atom, and Xb represents an oxygen atom when Yb 
represents an oxygen atom and 
denotes a single bond,
or Xb represents a group xe2x80x94CHxe2x95x90CHxe2x80x94 when Yb represents a CH group and 
denotes a double bond,
which compounds of formula (II/1) are reacted with (EtO)2POCH2CN to yield compounds of formula (II/2): 
wherein Hal, Xb and Yb are as defined hereinbefore,
which compounds of formula (II/2) are first subjected to the action of a reducing agent conventional in organic chemistry and then reacted with NaNH2, to yield compounds of formula (II/3): 
wherein Xb and Yb are as defined hereinbefore,
which compounds of formula (II/3) may be treated under the same conditions as the compounds of formula (V/a),
either with a compound of formula (VI), then (VIIIa) or (VIIIb), and then (VIIIc), to yield, in succession, compounds of formulae (I/3a), (I/3b) and (I/3c): 
wherein Xb, Yb, T, Rxe2x80x21 and Rxe2x80x22 are as defined hereinbefore,
or with a compound of formula (IX), the resulting product then being treated in the same manner as the compounds of formulae (X) and (XI), and then subjected to the successive action of a compound of formula (XIII) then (XV), as described hereinbefore, to yield compounds of formula (I/3d): 
wherein Xb, Yb, n1, R1 and R2 are as defined hereinbefore,
which compounds (I/a) to (I/o) and (I/3a) to (I/3d) constitute the totality of the compounds of the invention, which are purified, if necessary, according to a conventional purification technique, which may be separated, if desired, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into their addition salts with a pharmaceutically acceptable acid or base.
The compounds of formulae (II), (II/1), (III), (VI), (VIIIa), (VIIIb), (VIIIc), (IX), (XIII), (XV) and (XVI) are either known products or are obtained starting from known substances according to conventional processes of organic chemistry.
The compounds of the present invention are inhibitors of serotonin, noradrenalin and dopamine reuptake. They are useful as medicaments in the treatment of depression, panic attacks, obsessive-compulsive disorders, phobias, impulsive disorders, drug abuse, anxiety, obesity and bulimia.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), an optical isomer, or an addition salt thereof with a pharmaceutically acceptable acid or base, alone or in combination with one or more inert, non-toxic pharmaceutically acceptable excipients or carriers.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and especially tablets or dragxc3xa9es, sublingual tablets, soft gelatin capsules, hard gelatin capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nose drops, etc.
The useful dosage varies according to the age and weight of the patient, the route of administration, the nature and severity of the disorder, and whether any associated treatments are being taken and ranges from 0.5 mg to 25 mg in one or more administrations per day.
The following Examples illustrate the invention but do not limit it in any way. The starting materials used are known products or are prepared according to known procedures. The various Preparations yield synthesis intermediates for use in the preparation of the compounds of the invention.
The structures of the compounds described in the Examples were determined according to the usual spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, etc.).
The melting points were determined using a Kofler hot plate (K.), or using a hot plate under a microscope (M.K.). When the compound is present in the form of a salt, the melting point given corresponds to that of the salt product.
By way of information, the numbering adopted for the various tricyclic systems is as follows: 
Step 1
To a suspension of 13.5 g of 1-cyano-5-aminobenzocyclobutane in 400 ml of 1,2-dichloroethane there are added rapidly, dropwise, 26.5 ml of a 45% solution of 2,2-dimethoxyacetaldehyde in tert-butyl methyl ether, then 16 ml of acetic acid and finally, in fractions, 39.7 g of sodium triacetoxyborohydride. After increasing the temperature to 29xc2x0 C., the mixture is cooled again to room temperature, and then stirred for 1 hour 15 minutes and hydrolysed by pouring into 500 ml of an aqueous saturated sodium hydrogen carbonate solution. The organic phase is separated off, washed with water and concentrated under reduced pressure to yield the desired product in a quantitative yield.
Step 2
A solution prepared starting from 21.6 g of the product obtained in the preceding Step 1, 58 ml of pyridine and 225 ml of dichloromethane is cooled to 0xc2x0 C. 10.8 ml of mesyl chloride are added dropwise over the course of 20 minutes and stirring is carried out for a further 40 minutes at 0xc2x0 C. and then for 20 hours at room temperature. The reaction mixture is then poured into 40 ml of an aqueous saturated sodium hydrogen carbonate solution. After decanting, the aqueous phase is extracted twice with 150 ml of methylene chloride each time. The combined organic phases are washed with 1N hydrochloric acid, dried and concentrated to yield the expected product in a quantitative yield.
Step 3
A solution of 10.9 ml of titanium chloride in 450 ml of toluene and a solution of 27.9 g of the product obtained in Step 2 diluted in 450 ml of toluene are poured simultaneously over the course of 1 hour 15 minutes into 2.1 liters of toluene at reflux. When the addition is complete, the temperature is left to drop to 40xc2x0 C., and the mixture is poured into 1.8 liters of an aqueous saturated sodium hydrogen carbonate solution. After decanting, the aqueous phase is extracted with toluene, and the organic phases are combined, washed, dried and concentrated. The residue is purified by chromatography over silica gel (dichloromethane/cyclohexane: 75/25) to yield the expected product and its regioisomer.
Melting point: 142-144xc2x0 C. (MK)
2.6 g of the product of Preparation 1 are introduced into a solution of 7.7 g of potassium hydroxide in 190 ml of methanol. After 12 hours at reflux, the methanol is removed by evaporation and the residue is taken up in ether. After washing, the organic phase is dried and concentrated to yield the expected product.
Melting point: 126-128xc2x0 C. (MK)
3.43 g of the product obtained in Preparation 2 are dissolved in 55 ml of acetic acid. 3.84 g of sodium cyanoborohydride are added in portions over the course of 5 minutes to the reaction mixture which has been cooled to 13xc2x0 C. After returning to room temperature, stirring is maintained for 2 hours, and then the reaction mixture is cooled to 0xc2x0 C. and brought to pH=11 by the addition of a sodium hydroxide solution (45 g in 250 ml of water). The resulting milky solution is extracted with ether. The organic phases are washed, dried and concentrated to yield the expected product in the form of a white solid.
Melting point: 85-87xc2x0 C. (MK)
The regioisomer obtained in Step 3 of Preparation 1 corresponds to the expected product.
Melting point: 118-120xc2x0 C. (MK)
The product is obtained according to the process of Preparation 2, using the product of Preparation 4 as substrate.
Melting point: 132-134xc2x0 C. (MK)
The product is obtained according to the process of Preparation 3, using the product of Preparation 5 as substrate.
Step 1
Into 3.5 liters of liquid ammonia at reflux containing catalytic amounts of potassium ferrocyanide and iron trinitrate monohydrate there are introduced, over the course of 2 hours, 50.8 g of sodium, followed, over the course of 5 minutes, by 153 g of 3-(2-chloro-5-thiomethylphenyl)propionitrile. The mixture is left to react for 1 hour at xe2x88x9233xc2x0 C. and then 118.2 g of solid ammonium chloride are introduced. After removal of the ammonia by evaporation, the residue is taken up in ether, the salts are filtered off and the filtrate is evaporated to dryness, enabling the expected product to be obtained.
Step 2
11 g of the product of the preceding Step 1 are dissolved in 70 ml of dichloromethane. Onto the solution, which has been cooled to xe2x88x925xc2x0 C., there is poured a solution of 15.8 g of m-chloroperbenzoic acid in 80 ml of dichloromethane. After 10 minutes"" stirring, the reaction mixture is poured into 100 ml of water and 100 ml of 1N sodium hydroxide solution. Decanting is carried out, and the aqueous phase is extracted again with dichloromethane. The combined organic phases are washed with sodium hydrogen sulphate, and then with 1N sodium hydroxide solution, with sodium hydrogen carbonate and finally with water until neutral. The organic phase is dried and concentrated to yield the expected product.
Step 3
9.76 ml of trifluoroacetic acid dissolved in 20 ml of dichloromethane are added to a solution of 11 g of the product obtained in the preceding Step in 100 ml of dichloromethane. The addition lasts for 45 minutes, during which time the temperature is maintained at 25xc2x0 C. The reaction mixture is stirred again for 1 hour 30 minutes at that temperature, and then evaporated to dryness. The residue is taken up by stirring for 10 minutes in the presence of a 50/50 mixture of triethylamine and methanol. After evaporation, the residue is diluted with dichloromethane, washed with a saturated ammonium chloride solution and then with water, dried and concentrated to obtain the expected product in the form of an oil.
Step 4
3.65 g of sodium borohydride are added in portions, at 20xc2x0 C., to a solution of 9.1 g of the product obtained in the preceding Step 3 in 20 ml of tetrahydrofuran and 140 ml of ethanol. After 1 hour at 50xc2x0 C., 2.14 g of solid sodium borohydride are added again. The reaction mixture is then heated to 80xc2x0 C. and, at that temperature, 39 ml of bromoacetaldehyde diethylacetal are poured in over the course of 1 hour. Heating is maintained for a further 12 hours, and then the cooled reaction mixture is poured into 1 liter of ice-cold water. The resulting mixture is extracted with ether and the organic phase is washed with a 10% sodium hydrogen carbonate solution and then with water. The ethereal phase is dried and concentrated in vacuo to yield the expected product in the form of an oil.
Step 5
10 g of polyphosphoric acid, and 8.5 g of the product obtained in the preceding Step 4 in 500 ml of chlorobenzene are heated at 130xc2x0 C. for 4 hours. After cooling, the supernatant is drawn off and the residue is rinsed with dichloromethane. The supernatant and the dichloromethane phase are combined and neutralised by adding powdered sodium hydrogen carbonate. After 15 minutes"" stirring, filtration is carried out, followed by evaporation to dryness. The residue is purified by chromatography over silica gel (cyclohexane/dichloromethane: 50/50), enabling the expected product and a by-product to be obtained.
Melting point: 102-103xc2x0 C. (MK)
The product is obtained according to the process of Preparation 7, Steps 1 to 5, but in Step 1 using 3-(3-bromo-4-thiomethylphenyl)propionitrile instead of 3-(2-chloro-5-thiomethylphenyl)propionitrile.
Step 1
A solution of 16.5 g of 1-cyano-4-hydroxybenzocyclobutane in 205 ml of dimethylformamide is poured into a suspension of 67.8 mmol of sodium hydride in 160 ml of dimethylformamide. The reaction mixture is stirred for 30 minutes and then a solution of 10.2 ml of 1-bromo-2,2-diethoxyethane in 40 ml is added over the course of 15 minutes and the temperature is then maintained at 60xc2x0 C. for 6 hours. The mixture is stirred for a further 12 hours, the dimethylformamide is removed by evaporation, and the residue is taken up in water, extracted with dichloromethane, dried and concentrated in vacuo. The residue is chromatographed over silica gel (CH2Cl2/AcOEt: 95/5), enabling the expected product to be isolated.
Step 2
The product is obtained as in Step 3 of Preparation 1, but using the product of the preceding Step 1. In the course of chromatography over silica gel (CH2Cl2/cyclohexane: 80/20), the expected product and a by-product are isolated.
The product is obtained in the same manner as the product of Preparation 9, but in Step 1 using 1-cyano-5-hydroxybenzocyclobutane and in Step 2 using the mixture CH2Cl2/cyclohexane: 75/25 as eluant for the separation of the regioisomers. The expected product is isolated in the form of an oil.
The by-product obtained in Step 5 of Preparation 7 corresponds to the expected product.
The product is obtained in the course of Step 5 of Preparation 8.
The by-product obtained in Step 2 of Preparation 9 corresponds to the expected product.
The by-product isolated in the course of the chromatography of Preparation 10 corresponds to the expected product.
46 g of 3-(6-bromo-1,3-benzodioxol-5-yl)propanenitrile are introduced in portions into 1.4 liters of liquid ammonia in which there is dissolved sodium azide which was prepared previously by the introduction of 16.7 g of sodium into the liquid ammonia. After 30 minutes"" contact, the reaction mixture is treated with 38.7 g of ammonium chloride, and then the ammonia is distilled off at room temperature. The residue is taken up in ether and filtered; the precipitate is washed with ether. The combined ethereal phases are evaporated and the resulting residue is recrystallised from isopropyl alcohol, enabling the expected product to be isolated.
Melting point: 91xc2x0 C. (M.K.)
Step 1
The product is obtained according to the process of Step 1 of Preparation 9 using 1-cyano-6-hydroxybenzocyclobutane as substrate.
Step 2
The product is obtained according to the process of Step 3 of Preparation 1 using the product obtained in the preceding Step 1 as substrate.
The product is obtained according to the process of Preparation 15 using 3-(3-iodo-2-naphthyl)propionitrile as substrate.
Melting point: 98-102xc2x0 C. (M.K.)
Step 1
9.4 g of sodium amide are introduced into 350 ml of tetrahydrofuran. 25.9 g of 1-bromonaphthalene and 28 g of freshly prepared 1,1-diethoxyethylene are poured in succession into that mixture. The reaction mixture is refluxed for 16 hours and than taken up in water and ether. After washing the organic phase to neutral pH and drying thereof, the expected product is isolated and chromatographed over silica gel (dichloromethane/cyclohexane: 1/1).
Step 2
10 g of the product obtained in Step 1 are treated at room temperature with 42 ml of 1N hydrochloric acid dissolved in 170 ml of tetrahydrofuran. After 1 hour 30 minutes"" contact, the solvent is concentrated and the residue is poured into 170 ml of water. 6.9 g of a solid corresponding to the expected product are then isolated.
Melting point: 92-94xc2x0 C. (M.K)
Step 3
1.4 g of sodium borohydride are added to a suspension, at 0-5xc2x0 C., of 5.2 g of the product obtained in Step 2 in 150 ml of methanol. After 15 minutes at that temperature and then 1 hour at room temperature, the reaction mixture is poured into 300 g of ice and extracted with dichloromethane. After customary treatment, 5.2 g of the expected product are isolated.
Melting point: 96-100xc2x0 C. (M.K.)
Step 4
5.1 g of the product obtained in Step 3, 14.2 g of triphenylphosphine, and 12 g of carbon tetrabromide in 150 ml of ether are refluxed for 2 hours. After cooling, the reaction mixture is filtered, concentrated, taken up in 50 ml of ether, filtered and evaporated. The 7.85 g of resulting residue are treated with 10.5 g of tetrabutylammonium cyanide in 150 ml of tetrahydrofuran. After 64 hours"" contact at room temperature, the reaction mixture is concentrated and taken up in ice and ether. After decanting, an oil is isolated, which is purified by chromatography over silica gel (dichloromethane), enabling the expected product to be isolated.
Melting point: 78-84xc2x0 C.
The product is obtained according to the process of Preparation 1, Steps 1 to 3, using 4-amino-1-cyanobenzocyclobutane in Step 1.
Melting point: 164-168xc2x0 C. (M.K.)
The product is obtained according to the process of Preparation 2 but using the product of Preparation 19 as substrate.
Melting point: 109-113xc2x0 C. (M.K.)
The product is obtained according to the process of Preparation 3 but using the product of Preparation 20 as substrate.
Melting point: 100-105xc2x0 C. (M.K.)